5-151856384-C-T

Position:

• chr5-151856384-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000274576.9(GLRA1):​c.477-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GLRA1 ENST00000274576.9 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.70

Genes affected

GLRA1 (HGNC:4326): (glycine receptor alpha 1) The protein encoded by this gene is a subunit of a pentameric inhibitory glycine receptor, which mediates postsynaptic inhibition in the central nervous system. Defects in this gene are a cause of startle disease (STHE), also known as hereditary hyperekplexia or congenital stiff-person syndrome. Multiple transcript variants encoding different isoforms have been found. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.4, offset of -34, new splice context is: acagcctccctgatgtgcAGatc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-151856384-C-T is Pathogenic according to our data. Variant chr5-151856384-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 487340.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.477-1G>A		splice_acceptor_variant		ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.477-1G>A		splice_acceptor_variant			NP_001139512.1
GLRA1	NM_001292000.2	c.228-1G>A		splice_acceptor_variant			NP_001278929.1
GLRA1	XM_047417105.1	c.525-1G>A		splice_acceptor_variant			XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.477-1G>A		splice_acceptor_variant		1	NM_000171.4	ENSP00000274576	P4
GLRA1	ENST00000455880.2	c.477-1G>A		splice_acceptor_variant		1		ENSP00000411593	A1
GLRA1	ENST00000462581.6	c.*235-1G>A		splice_acceptor_variant, NMD_transcript_variant		1		ENSP00000430595
GLRA1	ENST00000471351.2	n.760-1G>A		splice_acceptor_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452446 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 723300

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperekplexia 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences

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A homozygous 3’ splice site variation in the GLRA1 gene (chr5:151235945; C>T) that affects the invariant CT acceptor splice site of exon 5 (c.477-1G>A; ENST00000455880) was detected. This 3’ splice variation is considered pathogenic because it is not present in the 1000 Genomes database and has a minor allele frequency of less than 0.001% in the ExAC database. It is predicted to be damaging by the pathogenicity predication software such as MutationTaster and Human Splicing Finder. This region is conserved across species. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs762864856; hg19: chr5-151235945;